Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia
NCT ID: NCT01865617
Last Updated: 2022-05-25
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
204 participants
INTERVENTIONAL
2013-05-22
2021-03-26
Brief Summary
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Detailed Description
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I. To evaluate the feasibility and safety of adoptive T cell therapy using ex vivo expanded autologous CD8 positive (+) and CD4+ CD19 chimeric antigen receptor (CAR)-T cells for patients with advanced CD19+ B cell malignancies.
SECONDARY OBJECTIVES:
I. To determine the duration of in vivo persistence of adoptively transferred T cells, and the phenotype of persisting T cells.
II. To determine if adoptively transferred T cells traffic to the bone marrow and function in vivo.
III. To determine if the adoptive transfer of CD19 CAR-T cells results in depletion of CD19+ B cells in vivo as a surrogate for functional activity.
IV. To determine if the adoptive transfer of CD19 CAR-T cells has antitumor activity in patients with measurable tumor burden prior to T cell transfer.
V. To determine if the adoptive transfer of CD19 CAR-T cells is associated with tumor lysis syndrome.
OUTLINE: This is a phase I, dose-escalation study of autologous CD19 CAR T-cells followed by a phase II study.
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells intravenously (IV) over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
DOSE DENSE EXPANSION COHORT: An additional cohort will receive a second anti-CD19-CAR lentiviral vector-transduced autologous T cell infusion without additional lymphodepleting chemotherapy 10-21 days after the first infusion if adequate CD19 CAR-T cells can be produced and appropriate criteria are met.
After completion of study treatment, patients are followed up for at least 15 years.
Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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ALL (high tumor burden) dose level 1
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: high Dose level: 1 up to 2x105 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
ALL (high tumor burden) dose level 2
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: high Dose level: 2 up to 2x106 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
ALL (high tumor burden) dose level 3
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: high Dose level: 3 up to 2x107 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
ALL (low tumor burden) dose level 1
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: low Dose level: 1 up to 2x105 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
ALL (low tumor burden) dose level 2
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: high Dose level: 2 up to 2x106 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
CLL dose level 1
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: CLL Dose level: 1 up to 2x105 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
CLL dose level 2
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: CLL Dose level: 2 up to 2x106 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
CLL dose level 3
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: CLL Dose level: 3 up to 2x107 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
CLL (ibrutinib) dose level 2
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: CLL (ibrutinib) Dose level: 2 up to 2x106 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
NHL dose level 1
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: NHL Dose level: 1 up to 2x105 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
NHL dose level 2
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: NHL Dose level: 2 up to 2x106 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
NHL dose level 3
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: NHL Dose level: 3 up to 2x107 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
NHL (dose dense) dose level 2
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: NHL Dose level: 2 up to 2x106 EGFR+ cells/kg
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
Interventions
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Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
Given IV
Eligibility Criteria
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Inclusion Criteria
* Patients with CD19 expressing acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL)
* Ability to understand and provide informed consent
* Not human immunodeficiency virus (HIV) infected
INCLUSIONS FOR CAR-T CELL THERAPY
* Patients with:
* CLL who are beyond first remission and who have failed combination chemoimmunotherapy with regimens containing a purine analogue and anti-CD20 antibody or who were not eligible for such therapy; patients with CLL for whom ibrutinib is now standard first line therapy, must have progressed on ibrutinib; patients with fludarabine refractory disease are eligible; patients may be treated following allogeneic hematopoietic cell transplant (HCT); for the concurrent ibrutinib cohort, patients must agree to continue on or be restarted on ibrutinib and must not have had prior intolerance to ibrutinib that would prevent this; patients managed with prior dose reductions for toxicity will continue at the reduced dose for the remainder of this study
* Indolent NHL or mantle cell NHL who are beyond first remission and previously treated with chemoimmunotherapy or who were not eligible for such therapy; patients who have relapsed following autologous or allogeneic HCT are eligible
* Aggressive NHL such as diffuse large B-cell lymphoma (DLBCL), who have relapsed or have residual disease following treatment with curative intent; patients should have relapsed following, or not be eligible for high-dose therapy and autologous HCT; patients with chemotherapy refractory disease or marrow involvement or comorbidities precluding successful autologous HCT are eligible; patients may be treated following allogeneic HCT
* Patients with CD19 expressing, relapsed or refractory ALL
* Patients with one of the above diagnoses whose disease state does not qualify but who have prognostic indicators that suggest a high risk of progression of disease may be screened and undergo leukapheresis; enrollment for T cell therapy would require meeting the full disease state eligibility
* Confirmation of diagnosis
* Evidence of CD19 expression by immunohistochemistry or flow cytometry on any prior or current tumor specimen or high likelihood of CD19 expression based on disease histology
* Karnofsky performance status \>= 60%
* All patients of childbearing potential must be willing to use a contraceptive method before, during, and for at least two months after the T cell infusion
* Ability to understand and provide informed consent
Exclusion Criteria
* Patients requiring ongoing daily corticosteroid therapy at a dose of \> 15 mg of prednisone per day (or equivalent); pulsed corticosteroid use for disease control is acceptable
* Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the Principal Investigator (PI)
* Serum creatinine \> 2.5 mg/dL
* Serum glutamic oxaloacetic transaminase (SGOT) \> 5 x upper limit of normal
* Bilirubin \> 3.0 mg/dL
* Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing; those with a forced expiratory volume in one second (FEV1) of \< 50 % of predicted will be excluded
* Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected) \< 40% will be excluded
* Significant cardiovascular abnormalities as defined by any one of the following: New York Heart Association (NYHA) class III or IV congestive heart failure, clinically significant hypotension, uncontrolled symptomatic coronary artery disease, or a documented ejection fraction of \< 35%
* Uncontrolled active infection
18 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
Fred Hutchinson Cancer Center
OTHER
Responsible Party
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Alexandre Hirayama
Research Associate
Principal Investigators
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Jordan Gauthier
Role: PRINCIPAL_INVESTIGATOR
Fred Hutch/University of Washington Cancer Consortium
Locations
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Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Countries
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References
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Fiorenza S, Zheng Y, Purushe J, Bock TJ, Sarthy J, Janssens DH, Sheih AS, Kimble EL, Kirchmeier D, Phi TD, Gauthier J, Hirayama AV, Riddell SR, Wu Q, Gottardo R, Maloney DG, Yang JYH, Henikoff S, Turtle CJ. Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion. Nat Commun. 2024 Sep 27;15(1):8309. doi: 10.1038/s41467-024-52503-2.
Liang EC, Albittar A, Huang JJ, Hirayama AV, Kimble EL, Portuguese AJ, Chapuis A, Shadman M, Till BG, Cassaday RD, Milano F, Kiem HP, Riddell SR, Turtle CJ, Maloney DG, Gauthier J. Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL. Blood Adv. 2023 Nov 28;7(22):6990-7005. doi: 10.1182/bloodadvances.2023011399.
Juluri KR, Wu QV, Voutsinas J, Hou J, Hirayama AV, Mullane E, Miles N, Maloney DG, Turtle CJ, Bar M, Gauthier J. Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy. Blood Adv. 2022 Apr 12;6(7):2055-2068. doi: 10.1182/bloodadvances.2020004142.
Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
Gauthier J, Bezerra ED, Hirayama AV, Fiorenza S, Sheih A, Chou CK, Kimble EL, Pender BS, Hawkins RM, Vakil A, Phi TD, Steinmetz RN, Jamieson AW, Bar M, Cassaday RD, Chapuis AG, Cowan AJ, Green DJ, Kiem HP, Milano F, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies. Blood. 2021 Jan 21;137(3):323-335. doi: 10.1182/blood.2020006770.
Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Riddell SR, Maloney DG, Turtle CJ. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood. 2019 Aug 15;134(7):636-640. doi: 10.1182/blood.2019000905.
Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Gooley T, Li D, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Acharya UH, Cassaday RD, Chapuis AG, Dhawale TM, Hendrie PC, Kiem HP, Lynch RC, Ramos J, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood. 2019 Apr 25;133(17):1876-1887. doi: 10.1182/blood-2018-11-887067. Epub 2019 Feb 19.
Tuazon SA, Li A, Gooley T, Eunson TW, Maloney DG, Turtle CJ, Linenberger ML, Connelly-Smith LS. Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies. Transfusion. 2019 May;59(5):1773-1780. doi: 10.1111/trf.15178. Epub 2019 Feb 6.
Hay KA, Gauthier J, Hirayama AV, Voutsinas JM, Wu Q, Li D, Gooley TA, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Schoch G, Chapuis AG, Till BG, Kiem HP, Ramos JD, Shadman M, Cassaday RD, Acharya UH, Riddell SR, Maloney DG, Turtle CJ. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood. 2019 Apr 11;133(15):1652-1663. doi: 10.1182/blood-2018-11-883710. Epub 2019 Feb 6.
Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, Riddell SR, Maloney DG, Boeckh M, Turtle CJ. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018 Jan 4;131(1):121-130. doi: 10.1182/blood-2017-07-793760. Epub 2017 Oct 16.
Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016 Jun 1;126(6):2123-38. doi: 10.1172/JCI85309. Epub 2016 Apr 25.
Provided Documents
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Document Type: Study Protocol
Other Identifiers
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NCI-2013-00073
Identifier Type: REGISTRY
Identifier Source: secondary_id
2639
Identifier Type: -
Identifier Source: secondary_id
RG9213011
Identifier Type: OTHER
Identifier Source: secondary_id
2639.00
Identifier Type: -
Identifier Source: org_study_id
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